RNA seq of WT and IGF2 Knockout cells
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina NovaSeq 6000
ORGANISM(S): Homo sapiens
SUBMITTER: Martin Simon
PROVIDER: E-MTAB-14271 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:We identified an enhancer element near IGF2 locus that is possibly involved with dopamine function and schizophrenia. A knockout mouse was generated for the enhancer element in the IGF2 locus. We then characterized the striatal synaptosomes ( i.e. biological fraction representing pre- post synaptic nerve terminal)by mass spectometry from WT and Igf2 enhancer KO mice.
2019-05-31 | PXD012786 | Pride
Project description:Changes in microRNA expression in Igf2-p and H19-m mouse embryos (E9.5) were determined in order to assess whether perturbation of miR-483* and miR-675 in Igf2-p and H19-m mutants was likely to have contributed to a modification of tumour phenotype. The Igf2 gene contains miR-483* but the targeted deletion of Igf2-p in these mice spares the region encoding this microRNA. The H19 gene contains miR-675 and its expression was mono-allelelic in heterozygous H19-m mice as evidenced by a significant reduction in miR-675 in these mice relative to WT.
2011-12-01 | E-MTAB-873 | biostudies-arrayexpress
Project description:RNA seq of WT and IGF2 Knockout cells
| PRJEB77856 | ENA
Project description:The transcription factor nuclear factor-κB (NF-κB) has important roles for tumorigenesis, but how it regulates cancer stem cells (CSCs) remains largely unclear. We identified insulin-like growth factor 2 (IGF2) is a key target of NF-κB activated by HER2/HER3 signaling to form tumor spheres in breast cancer cells. The IGF2 receptor, IGF1 R, was expressed at high levels in CSC-enriched populations in primary breast cancer cells. Moreover, IGF2-PI3K (IGF2-phosphatidyl inositol 3 kinase) signaling induced expression of a stemness transcription factor, inhibitor of DNA-binding 1 (ID1), and IGF2 itself. ID1 knockdown greatly reduced IGF2 expression, and tumor sphere formation. Finally, treatment with anti-IGF1/2 antibodies blocked tumorigenesis derived from the IGF1Rhigh CSC-enriched population in a patient-derived xenograft model. Thus, NF-κB may trigger IGF2-ID1-IGF2-positive feedback circuits that allow cancer stem-like cells to appear. Then, they may become addicted to the circuits. As the circuits are the Achilles' heels of CSCs, it will be critical to break them for eradication of CSCs.
2016-09-05 | GSE64073 | GEO
Project description:Background and aims: Metabolic diseases, including diabetes, obesity, and dyslipidemia, are significant public health concerns worldwide. The insulin-like growth factor 2 (IGF2) gene have been implicated in various physiological processes, but its specific role in lipid metabolism remains unclear. We aim to elucidate the role of IGF2 in regulating lipid metabolism in adipose tissues and its association with metabolic syndrome (MetS). Methods: The research employed a multidisciplinary approach to investigate the role of IGF2 in lipid metabolism. We investigated the correlation between genetic variations within the IGF2 gene and metabolic parameters. We conduct a cross-sectional human study to evaluate relationships between varying IGF2 serum concentrations and the incidence of MetS. Additionally, manipulation of IGF2 expression levels in mouse and cell models via overexpression and knockdown to assess impacts on lipid metabolism in adipose tissue, specifically lipid accumulation, insulin resistance, and the balance between lipogenesis and lipolysis. Furthermore, the study employs metabolomics techniques to scrutinize the broader metabolic profiles in adipose tissues in response to IGF2 modulation. Results: Multiple SNP loci in the IGF2 gene were significantly associated with BMI, HbA1c, and diabetes. Insufficient or excessive expression of IGF2 was identified as a risk factor for hyperlipidemia, low HDL-c, and central obesity in MetS. We observed that IGF2 was mainly concentrated in adipose tissues and adipocytes. Enhanced IGF2 expression stimulated adipogenesis and lipid accumulation, whereas IGF2 knockdown hindered lipolysis, exacerbating ectopic lipid accumulation and insulin resistance. There is a substantial enlargement of pancreatic tissue and heightened insulin generation in mice deficient in IGF2. Activation of the PI3K/Akt pathway through IGF1R in IGF2 excess or INSR in conditions of IGF2 scarcity, along with inhibition of AMPK, implies a common downstream process that favors lipid accumulation and metabolic reprogramming in adipocytes. Conclusions: Our study demonstrated that upregulation of IGF2 enhanced adipogenesis and lipogenesis, while knockdown of IGF2 inhibited lipolysis, which resulting in accelerating lipid accumulation through PI3K/Akt-AMPK pathway.
2024-08-08 | GSE273546 | GEO
Project description:The genetic mechanisms that determine the size of the adult pancreas are not fully understood. Here we address the importance of the imprinted Igf2 gene for growth and function of the mouse pancreas. We used reporter lines to monitor Igf2 levels during late fetal and postnatal pancreatic development and demonstrate that Igf2 is mostly expressed within the mesenchyme. We manipulated Igf2 levels in vivo in the major pancreas cell types using Cre lines and found that loss of Igf2 from the developing mesenchyme results in pancreatic hypoplasia, associated with loss of acinar and beta-cell mass, postnatal whole-body growth restriction and maternal glucose intolerance during pregnancy. Overexpression of Igf2 directed to the mesenchyme results in pancreatic overgrowth. Importantly, deletion of Igf2 from the developing epithelium has no growth effects. Our findings demonstrate that a major role for Igf2 is the regulation of pancreas size, and reveal an unforeseen key function for mesenchymal IGF signalling in pancreatic growth.
2017-12-31 | GSE100981 | GEO
Project description:Background & Aims: Hepatocellular carcinoma (HCC) is a major health problem. Most patients are diagnosed at advanced stages when the only approved therapy is sorafenib. Consequently, there is an urgent need to develop effective treatments. IGF-signaling is aberrantly activated in HCC, but there is no clear understanding on the molecular drivers and potential therapeutic targets within the pathway. Since IGF2-ligand is overexpressed in HCC, we aimed to elucidate its mechanism of overexpression, assess its oncogenic potential in vitro and in vivo and determine the antitumoral efficacy of molecular therapies against IGF2. Methods: Expression profiling, miRNAs expression and methylation were analyzed in 228 HCCs focusing on IGF2. Stable HCC cell lines with knock-down and ectopic overexpression of IGF2 were generated. A chemically-induced mouse model of HCC, and genetically-engineered mouse models (GEMM) overexpressing IGF2 in the liver were generated to assess IGF2 oncogenicity. The therapeutic potential of the monoclonal antibody against IGF-ligands (IGF1/2-mAb) and its combination with sorafenib was tested in vitro and in a xenograft model. Results: IGF2-overexpression occurred in 15% of HCC patients as a result of the epigenetic reactivation of IGF2-fetal promoters, mainly through loss of promoter methylation. Re-expression of IGF2 was associated with progenitor cell-like and poorly differentiated HCCs, and with poor prognosis (p<0.0001). In the GEMM model, IGF2-overexpression accelerated HCC progression and reduced survival (p=0.02). Conversely, IGF2-blockage using IGF1/2- mAbs delayed tumor growth and increased survival in vivo (p<0.0001), through antiproliferative and antiangiogenic mechanisms. Conclusions: We propose IGF2 as the first actionable epi-driver in HCC, and IGF1/2-mAbs as a potential targeted therapy in a defined subset of HCC patients. Keywords: IGF2, HCC, epidriver, IGF-pathway, monoclonal antibody, BI 836845.
2019-08-05 | GSE85274 | GEO
Project description:Chronic kidney disease (CKD) is prevalent in 10% of world’s adult population, with Estimated Glomerular filtration rate (eGFR) and albuminuria employed in diagnosis. Role of protein glycosylation in causal mechanisms of CKD progression is largely unknown. Aim of this study was to identify urinary O-linked glycopeptides in association to CKD for better characterization of CKD molecular manifestations. Urine samples from 2 healthy and 8 CKD subjects were analyzed by CE-MS/MS and glycopeptide analysis using Proteome Discoverer 1.4. Distribution of identi-fied glycopeptides and correlation with Age, eGFR and Albuminuria were evaluated in 3810 da-tasets. In total, 17 O-linked glycopeptides from 7 different proteins were identified, derived primarily from Insulin-like growth factor-II (IGF2). Glycosylation occurred at the surface ex-posed IGF2 Threonine 96 position. Three glycopeptides (DVStPPTVLPDNFPRYPVGKF, DVStPPTVLPDNFPRYPVG and DVStPPTVLPDNFPRYP) exhibited positive correlation with Age. Glycopeptide (tPPTVLPDNFPRYP) showed strong negative association with eGFR. These results suggest that with aging and deteriorating kidney function, alterations in IGF2 proteoforms take place; which may reflect changes in mature IGF2 protein. Our results corroborate this hypothesis as IGF2 increased plasma levels were observed in CKD patients. Protease predictions, consider-ing also available transcriptomics data, suggest activation of cathepsin S with CKD, meriting further investigation.
2023-05-10 | PXD039829 | Pride
Project description:We tested whether loss of p53 function leads to insulin-like growth factor 2 (IGF2) pathway dependency in vivo in genetically defined mouse models. Unexpectedly we found lethality, due to post-natal lung haemorrhage, occurred in Igf2 paternal null allele female mice (Igf2-p) but only if derived from double heterozygote fathers (Igf2-p, p53+/-). Consequently we investigated the effects of paternal genotype (wild-type, Igf2-p and Igf2-p, p53+/-) on gene expression. Microarray gene expression profiling of whole mouse embryos (embryonic day 9.5) revealed that lethality was associated with a specific gene signature. Since double heterozygote female offspring (Igf2-p, p53+/-) of Igf2-p, p53+/- fathers did not have the lethality phenotype we identified gene expression changes associated with this 'rescue'. Supplementary information available when browsing all available files.
2012-06-01 | E-MTAB-1001 | biostudies-arrayexpress
Project description:Insulin-like growth factor 2 (Igf2) is the major fetal growth hormone in mammals. Here we identify the Kruppel-associated-box (KRAB) zinc finger protein 568 (ZFP568) as a direct repressor of a placental specific Igf2 transcript (designated Igf2-P0) in early mouse development. Loss of Zfp568, which leads to gastrulation failure, causes inappropriate Igf2-P0 activation. Strikingly, deletion of paternal Igf2 can completely rescue Zfp568 knockout-induced gastrulation phenotypes. Mechanistically, ZFP568 and its binding site are required to maintain H3K9me3 and CpG methylation of the Igf2-P0 region. The ZFP568 binding site upstream of the Igf2-P0 transcript is highly conserved throughout Eutheria, along with the DNA binding domain of ZFP568 orthologs, with the exception of human, whose three Znf568 alleles previously linked to human head size at birth have rapidly evolved and mostly lost the ability to bind and suppress Igf2, coincident with the loss of Igf2-P0 transcript activity. We speculate that the Igf2-P0 transcript and its repressor ZFP568 appeared in a common ancestor of placental mammals as a critical adaptation to boost Igf2 expression specifically in the placenta to regulate maternal supply and fetal demand for nutrients. These data also highlight the exquisite specificity and selectivity by which KRAB-ZFPs have been naturally selected to recognize their genomic targets for pinpoint heterochromatin establishment during mammalian evolution.
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